Endothelial-to-Mesenchymal Transition

1734 Pulmonary arterial hypertension (PAH) is a complex and progressive disorder, which almost always leads to right heart failure and death. PAH is invariably associated with a spectrum of structural changes in the pulmonary arteries: increased adventitial and medial thickness, eccentric and concentric intimal thickening, the obliteration and recanalization of arteries, and the appearance of dilation lesions. Virtually all these changes are characterized, to a greater or lesser degree, by increased numbers of cells expressing α-smooth muscle (SM) actin. However, neither the origins of these cells nor the molecular mechanisms operating to cause their accumulation have been fully elucidated. Traditionally, it has been thought that the α-SM-actin–expressing SM-like cells that accumulate in the above-mentioned vascular lesions were derived from the proliferative expansion of resident vascular media SM cells or adventitial fibroblasts through the processes of dedifferentiation of the former or differentiation of the latter. Through the years, however, this concept has been challenged by experimental data in not only the lung, but also in the heart, kidney, and liver, demonstrating many possible sources of α-SMactin–expressing cells, including differentiation of resident vascular progenitor cells, recruitment of circulating progenitors, or multifunctional inflammatory cells (fibrocytes), and finally the possibility that endothelial cells can transition into a mesenchymal SM-like phenotype in a process recapitulating their developmental capabilities. Studies by Ranchoux et al, and now by Hopper et al in this issue of Circulation, provide convincing experimental evidence that endothelialto-mesenchymal transition (EndMT) occurs in the setting of PAH/pulmonary hypertension in both humans and animal models and potentially constitutes a target against which specific therapeutic agents could be used to abrogate the process and improve the status of the patient with PAH.